Tumor intrinsic activity of Chromobox 2 (CBX2) remodels the tumor microenvironment in high grade serous carcinoma.

ABSTRACT

Chromobox 2 (CBX2), an epigenetic reader and component of Polycomb Repressor Complex 1 (PRC1), is highly expressed in >75% of high-grade serous carcinoma (HGSC). Increased CBX2 expression is associated with poorer survival, while CBX2 knockdown leads to improved chemotherapy sensitivity. In an HGSC immune competent murine model, knockdown of CBX2 decreased tumor progression. We sought to explore the impact of modulation of CBX2 on the tumor immune microenvironment (TIME), understanding that the TIME plays a critical role in disease progression and development of therapy resistance. Exploration of existing datasets demonstrated that elevated CBX2 expression significantly correlated with the specific immune cell types in the TIME. RNA-seq and pathway analysis of differentially expressed genes demonstrated immune signature enrichment. Confocal microscopy and co-culture experiments found modulation of CBX2 leads to increased recruitment and infiltration of macrophages. Flow cytometry of macrophages cultured with CBX2 overexpressing cells showed increased M2-like macrophages and decreased phagocytosis activity. Cbx2 knockdown in the Trp53, Brca2 null ID8 syngeneic murine model (ID8 Trp53-/- Brca2-/-) led to decreased tumor progression compared to control. NanoString Immuno-Oncology Panel analysis suggested knock down in Cbx2 shifts immune cell composition, with an increase in macrophages. Multispectral immunohistochemistry further confirmed an increase in macrophage infiltration. Increased CBX2 expression leads to recruitment and polarization of pro-tumor macrophages and targeting CBX2 may serve to modulate the TIME to enhance the efficacy of immune therapies.